Brain metastasis (BM) is one of the most common types of metastases in patients with non-small cell lung cancer (NSCLC) and poses a great threat to survival and quality of life for patients.[1,2] Approximately 20% of NSCLC patients are initially diagnosed with BM, and BM may occur in 20% to 50% of NSCLC patients.[3,4] Epidermal growth factor receptor (EGFR) gene mutations are common among NSCLC patients, with the frequency of approximately 50% in Asian patients and 10% to 20% in Caucasian patients;[5-7] and patients with EGFR-sensitive mutations have a higher propensity to develop BM than those who are negative.[8,9] Compared with chemotherapy, EGFR tyrosine kinase inhibitor (TKI) therapy significantly prolongs overall survival (OS) in metastatic EGFR-mutated NSCLC patients. For symptomatic and uncontrolled BM, local therapy is recommended as the first-line treatment. For stable BM, which refers to clinically asymptomatic and controlled BM, systemic therapy is recommended.
Several EGFR-TKIs are recommended for the first-line therapy in metastatic EGFR-mutated NSCLC, such as first-generation EGFR-TKIs (gefitinib, erlotinib, and icotinib), second-generation EGFR-TKIs (dacomitinib and afatinib), and third-generation EGFR-TKIs (osimertinib). Combined therapy of EGFR-TKIs and other drugs (antiangiogenic drugs and chemotherapy) has also been established as a first-line treatment to enhance efficacy and overcome drug resistance. Because of the blood–brain barrier, patients with BM have a poor intracranial response to chemotherapy and first-/second-generation EGFR-TKIs. The penetration (cerebral spinal fluid [CSF]/plasma or CSF/blood) of first-generation and second-generation EGFR-TKIs was only 1.1% to 3.3% and 1.7%, respectively. The BRAIN study indicated that icotinib might be better for patients with EGFR-mutated NSCLC accompanied by multiple BM, with a significantly longer intracranial progression-free survival (PFS) than whole-brain radiation therapy plus chemotherapy. However, no difference in OS was observed in this study. A preclinical study indicated that compared with other EGFR-TKIs, osimertinib provided markedly greater central nervous system activity in EGFR-mutated NSCLC BM models. The penetration (CSF/plasma or CSF/blood) of osimertinib was 2.5–16.0%, and the objective response rate (ORR) was 76%. However, in the subgroup analysis of FLAURA, osimertinib only showed a favorable trend in OS.[16,17] The combination of first-generation TKIs with antiangiogenic agents and chemotherapy improved PFS in advanced, EGFR-mutated NSCLC patients, even in those with BM.[18,19] However, the existing data on treatments for BM are mostly derived from subgroup analyses, lacking phase III studies and direct comparisons. Therefore, the optimal first-line therapy in NSCLC patients carrying EGFR-sensitive mutations with stable BM remains controversial. In addition, the prognosis of patients with BM is poorer than that of patients without BM. Hence, regimens should be selected according to the BM status. To address these questions, we conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) by comparing a number of interventions with diverse contrasts simultaneously, which is widely used in the absence of head-to-head trial data, to gain insight into the relative efficacy of first-line regimens in advanced EGFR-mutated NSCLC patients with and without BM.
Database and search strategy
RCTs focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR-mutant NSCLC patients, who have not received systematic treatment, were systematically searched from the PubMed, Cochrane Library, and EMBASE with the terms NSCLC, EGFR, TKI, first-line, PFS, OS, and RCT up to December 31, 2021. Detailed search strategies are available in Supplementary Table 1, https://links.lww.com/CM9/B524. To acquire data from unpublished trials, abstracts presented at the conferences of the American Society of Clinical Oncology and the European Society for Medical Oncology in 2021 were further searched. This protocol was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on October 06, 2020, and it was last updated on October 06, 2020 (registration number INPLASY2020100018).
The primary and secondary outcomes in this study were PFS and OS, respectively.
To guarantee transitivity, trials with strict criteria for patient grouping were identified and included. Studies that met all of the following inclusion criteria were included in the final analysis: (1) study patients: advanced or metastatic NSCLC with EGFR-sensitive mutations; (2) interventions: EGFR-TKIs with or without anti-vascular endothelial growth factor receptor or chemotherapy; (3) contrasts: chemotherapy or EGFR-TKIs; (4) outcomes: PFS and/or OS; and (5) study design: RCT.
We excluded studies according to the exclusion criteria: (1) without EGFR-mutant patients; (2) without the intervention of EGFR-TKIs; (3) without survival outcome; (4) non-first-line therapy; (5) comment, review, protocol, or editor opinion; and (6) duplicated studies.
Data extraction and risk assessment for bias
Based on eligibility criteria initially predefined by our research working group, the titles and abstracts of identified records were screened, and then the full texts of potentially eligible studies were further assessed. For the final included studies, our research group extracted the data and conducted a risk assessment. A form was pre-designed by a review working group for data extraction, including the following information: (1) basic information: first author, year of publication, and country; (2) trial design: design types, population characteristics, sample size, and treatments in the control and intervention groups, and (3) outcomes: data on PFS and OS.
We used the Cochrane risk-of-bias tool to evaluate allocation concealment (selection bias), random sequence generation (selection bias), blinding of outcome assessment (detection bias), blinding of participants and personnel (performance bias), selective reporting (reporting bias), incomplete outcome data (attrition bias), and other biases.
The random-effect model was adopted for the analysis. The hazard ratios (HRs) and the associated standard errors of OS and PFS were used for NMA. The network plots were produced using Stata software (version 15.0, StataCorp LLC, College Station, TX, USA) to suggest interactions among the evaluated regimens from the included trials. Heterogeneity across the included studies was assessed by the Q test and I2 statistics. I2 values <25%, 25% to 50%, and >50% indicated low, moderate, or high heterogeneity, respectively.
The Bayesian framework was used with a Markov chain Monte Carlo simulation technique with R software (version 3.6.3, https://www.r-project.org/). In addition, we applied the HRs and 95% CI to compare the intervention measures. Owing to the limited number of included studies and the lack of direct comparisons for most evaluated interventions, a random-effect model was used using the “gemtc” and “rjags” packages. To fit the model, we set four different series of initial values for five kinds of parameters, including the number of chains, tuning iterations, simulation iterations, and thinning intervals. For both PFS and OS, our analysis generated 10,000 sample iterations with 5000 burn-ins and a thinning interval of 5. Using visual inspection of the four chains, we estimated the convergence of iterations to establish homogenous parameter estimation through the density plot. Under the Bayesian framework, overall rankings of therapies were estimated. For the ranking, higher cumulative probability means better regimen. Transitivity and consistency are two key assumptions that had to be met to conduct the NMA. To guarantee transitivity, trials with strict criteria for patient allocation were identified and included, and the same condition for evaluated treatments was optimized. Model fit was assessed by examining the posterior deviance information criterion (DIC). We performed a weighted integration of the evidence through fitting random- effects NMA models. Inconsistency was assessed by comparing the DICs of our primary analyses (based on NMA models that assume consistency between direct and indirect evidence) and the DICs yielded by inconsistency models (which provide effect estimates based on direct evidence only) by using the node-splitting procedure for all loops.
We identified 4841 unique records from the dataset, 4534 articles were excluded by initial title and abstract screening, and 307 articles were retrieved and reviewed. Finally, a total of 17 RCTs with 5077 patients were included in this study [Figure 1], among which 12 studies included 825 patients with BM, while 17 studies included 4252 patients without BM [Table 1].[16-19,25-40] A total of 12 intervention treatments, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT), were finally included.
Table 1 -
Baseline characteristics of studies included in the NMA.
||Year (patients register)
||Clinical trial number
||Sample size (n/n)
||Median age (years)
||SoC + bevacizumab
||SoC + PbCT
|Noronha et al
||SoC + PbCT
|Han et al
||SoC + PbCT
||SoC + bevacizumab
||SoC + bevacizumab
||SoC + ramucirumab
||SoC + apatinib
||Osimertinib + bevacizumab
||SoC + bevacizumab
Data are expressed as intervention/control unless indicated otherwise. ∗Mean age. †The Median of age and the proportion of sex of different treatments came from all patients.BM: Brain metastases; EGFR: Epidermal growth factor receptor; NA: Not available; NMA: Network meta-analysis; OS: Overall survival;PbCT: pemetrexed based chemotherapy; PfCT: pemetrexed free chemotherapy; PFS: Progression-free survival; SoC: Standards of care, including gefitinib, erlotinib, and icotinib.
Risk of bias
The risk of bias assessment for included studies was mainly performed according to the Cochrane handbook. There is a low to medium risk of bias [Figure 2]. All included studies described the method used to generate the allocation sequence, concealed the allocation sequence, and reported the related outcomes based on the trial protocol and other potential biases [Figure 2]. No significant bias was found in most studies, except trial NCT01466660 (Lung 7), which had a high risk of bias in terms of completeness because of the inconsistent number of patients. In this study, there were 50 patients with BM in the baseline demographics, but there were 51 patients in the subgroup analyses. Furthermore, most studies did not clearly state the method for blinding in terms of the intervention.
Network meta-analysis of the efficacy of different treatments
This NMA identified 15 studies for PFS and 12 studies for OS. In patients with BM, there were nine and seven studies with PFS [Figure 3A] and OS [Figure 3B] outcomes, respectively. For patients without BM, 15 studies reported PFS [Figure 3C], while 12 studies included OS outcomes [Figure 3D].
PFS for all advanced, EGFR-mutant NSCLC patients
Compared with afatinib, SoC, PbCT, and PfCT, osimertinib was associated with better PFS for all patients with advanced and EGFR-mutant NSCLC (HR = 0.62, 95% CI: 0.43–0.89; HR = 0.47, 95% CI: 0.36–0.59; HR = 0.31, 95% CI: 0.17–0.51; HR = 0.16, 95% CI: 0.10–0.24; Figure 4A). Compared with SoC + apatinib, afatinib, SoC, PbCT, and PfCT, SoC + PbCT improved the PFS of all patients with advanced and EGFR-mutant NSCLC (HR = 0.66, 95% CI: 0.46–0.99; HR = 0.63, 95% CI: 0.44–0.87; HR = 0.47, 95% CI: 0.38–0.57; HR = 0.31, 95% CI: 0.18–0.49; HR = 0.16, 95% CI: 0.10–0.23; Figure 4A). Osimertinib + bevacizumab, aumolertinib, SoC + PbCT, osimertinib, SoC + apatinib, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib all showed superior efficacy in PFS for all advanced, EGFR-mutant NSCLC patients compared with SoC (HR = 0.42, 95% CI: 0.23–0.77; HR = 0.47, 95% CI: 0.35–0.62; HR = 0.47, 95% CI: 0.38–0.57; HR = 0.47, 95% CI: 0.36–0.59; HR = 0.71, 95% CI: 0.50–0.98; HR = 0.62, 95% CI: 0.47–0.82; HR = 0.64, 95% CI: 0.48–0.85; HR = 0.60, 95% CI: 0.50–0.73; HR = 0.75, 95% CI: 0.58–0.99), PbCT (HR = 0.27, 95% CI: 0.12–0.60; HR = 0.31, 95% CI: 0.17–0.52; HR = 0.31, 95% CI: 0.18–0.49; HR = 0.31, 95% CI: 0.17–0.51; HR = 0.47, 95% CI: 0.26–0.80; HR = 0.42, 95% CI: 0.24–0.68; HR = 0.43, 95% CI: 0.25–0.71; HR = 0.40, 95% CI: 0.24–0.62; HR = 0.59, 95% CI: 0.35–0.70), and PfCT (HR = 0.14, 95% CI: 0.07–0.27; HR = 0.16, 95% CI: 0.10–0.24; HR = 0.16, 95% CI: 0.10–0.23; HR = 0.16, 95% CI: 0.10–0.24; HR = 0.24, 95% CI: 0.15–0.38; HR = 0.21, 95% CI: 0.14–0.35; HR = 0.21, 95% CI: 0.14–0.33; HR = 0.20, 95% CI: 0.14–0.29; HR = 0.25, 95% CI: 0.18–0.35). Aumolertinib, SoC + PbCT, osimertinib, and SoC + ramucirumab showed superior efficacy in PFS for all advanced, EGFR-mutant NSCLC patients compared with afatinib (HR = 0.62, 95% CI: 0.41–0.90; HR = 0.63, 95% CI: 0.44–0.87; HR = 0.62, 95% CI: 0.43–0.89; HR = 0.49, 95% CI: 0.35–0.70), and SoC + PbCT showed superior efficacy than SoC + apatinib (HR = 0.66, 95% CI: 0.46–0.99). No statistical difference was observed in PFS between PbCT and SoC (HR = 1.50, 95% CI: 0.99–2.46), but both regimens showed favorable PFS compared with PfCT (SoC vs. PfCT, HR = 0.33, 95% CI: 0.24–0.47; PbCT vs. PfCT, HR = 0.50, 95% CI: 0.32–0.85). Additionally, there were no significant differences in PFS in all advanced, EGFR-mutant NSCLC patients treated with osimertinib + bevacizumab, aumolertinib, SoC + PbCT, or osimertinib; there were also no significant differences in SoC + apatinib, dacomitinib, SoC + ramucirumab, and SoC + bevacizumab [Figure 4A].
PFS for advanced and EGFR-mutant NSCLC patients with or without BM
SoC + PbCT improved PFS in patients with brain metastases compared with SoC (HR = 0.40, 95% CI: 0.17–0.95; Figure 4B). There were no obvious differences were found among osimertinib + bevacizumab, aumolertinib, and SoC + PbCT [Figure 4B]. For patients without BM, the results were similar to the findings in all patients [Figure 4C]. Osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20–0.90; HR = 0.46, 95% CI: 0.31–0.68; HR = 0.51, 95% CI: 0.34–0.77; HR = 0.50, 95% CI: 0.38–0.66; HR = 0.62, 95% CI: 0.43–0.89; HR = 0.64, 95% CI: 0.44–0.94; HR = 0.61, 95% CI: 0.48–0.76; HR = 0.71, 95% CI: 0.50–1.00), PbCT (HR = 0.29, 95% CI: 0.11–0.74; HR = 0.31, 95% CI: 0.15–0.62; HR = 0.34, 95% CI: 0.17–0.69; HR = 0.34, 95% CI: 0.18–0.64; HR = 0.42, 95% CI: 0.21–0.82; HR = 0.43, 95% CI: 0.22–0.87; HR = 0.41, 95% CI: 0.22–0.74; HR = 0.48, 95% CI: 0.31–0.75), and PfCT (HR = 0.14, 95% CI: 0.06–0.32; HR = 0.15, 95% CI: 0.09–0.26; HR = 0.17, 95% CI: 0.09–0.29; HR = 0.16, 95% CI: 0.10–0.26; HR = 0.21, 95% CI: 0.12–0.35; HR = 0.21, 95% CI: 0.12–0.39; HR = 0.20, 95% CI: 0.12–0.31; HR = 0.23, 95% CI: 0.16–0.34) in terms of PFS in patients without BM. SoC + apatinib showed relatively superior PFS in patients without BM compared with PbCT (HR = 0.44, 95% CI: 0.22–0.92) and PfCT (HR = 0.21, 95% CI: 0.12–0.39), but presented a similar effect with SoC (HR = 0.65, 95% CI: 0.42–1.03). There was no observed statistical difference in PFS in patients without BM treated with PbCT or SoC (HR = 1.49, 95% CI: 0.84–2.64), but both showed favorable PFS compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06–4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06–0.32). In addition, no significant differences were observed among patients without BM treated with osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, SoC + apatinib, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, or afatinib [Figure 4C].
OS for all advanced, EGFR-mutant NSCLC patients
SoC + PbCT had superior OS compared with SoC (HR = 0.61, 95% CI: 0.43–0.84) and PfCT (HR = 0.57, 95% CI: 0.33–0.91), and SoC + bevacizumab had superior OS compared with SoC (HR = 0.69, 95% CI: 0.55–0.89) [Figure 4D]. There were not significant differences in others treatments.
OS for advanced and EGFR-mutant NSCLC patients with or without BM
For patients with BM, no significant differences in OS were found among all treatments [Figure 4E]. For patients without BM, SoC + PbCT (HR = 0.64, 95% CI: 0.36–1.14) and SoC + bevacizumab (HR = 0.70, 95% CI: 0.47–1.09) seemed to have a trend of benefit for OS compared with SoC, but no significant differences were found for other treatments [Figure 4F].
Ranking of treatment regimens
Bayesian ranking profiles of all evaluated treatment regimens in different populations are shown in Figure 5. In terms of PFS, both in all patients and without BM patients, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 51.2% and 47.1%, respectively. For those with BM, osimertinib + bevacizumab ranked the first for PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For OS, in all patients and patients with or without BM, SoC + PbCT was most likely to rank the first, with cumulative probabilities of 58.4%, 46.8%, and 37.3%, respectively.
Heterogeneity and inconsistency assessment
Most comparisons from one or two studies, minor heterogeneities could be found. However, high heterogeneities could be found from the comparisons between PfCT and afatinib (51.90%) for PFS in all patients, and SoC + bevacizumab and SoC for PFS in patients with brain metastases (60.60%). The fit of the consistency model was used in the analysis due to the superiority of lower DIC than that from the inconsistency model. Differences between the consistency model and the inconsistency model were accepted (less than 5 [Supplementary Table 2, https://links.lww.com/CM9/B524]). No significant differences were found between direct and indirect estimates for any outcome (P >0.05) [Supplementary Table 3, https://links.lww.com/CM9/B524].
The brain is a common metastatic site in patients with NSCLC, resulting in a relatively poor prognosis. Despite the rapid development of treatment agents—EGFR-TKIs for NSCLC, their efficacy is poorer in advanced, EGFR-mutant, BM NSCLC patients than in those without BM. Patients with EGFR-mutated NSCLC are prone to develop BM, and the medical demands for patients with BM are largely unmet. Therefore, the status of BM should be considered in clinical practice while selecting the optimal treatment. A few NMAs have drawn conclusions regarding the optimal therapy in EGFR-mutated NSCLC, but no data have indicated the preferable approach for BM patients. Additionally, some combined regimens of osimertinib + bevacizumab, first-generation EGFR-TKIs with antiangiogenic drugs or chemotherapy were not included into analysis, and OS data from the FLAURA, JO25567, and NEJ026 studies and updated results from the CTONG 1509, RELAY, ACTIVE, AENEAS, and WJOG9717L studies were not disclosed in previously NMAs.[43,44] Thus, we performed a NMA to investigate the survival outcomes of advanced EGFR-mutated NSCLC patients with different BM statuses and therapeutic regimen to identify the optimal therapeutic strategy. To our knowledge, this meta-analysis included the largest sample size to date and involved mostly current regimens to evaluate the optimal therapy for EGFR-mutated NSCLC patients with BM. Furthermore, this NMA identified the optimal EGFR-TKI regimen for non-BM, NSCLC patients.
A previous study showed that osimertinib has superior efficacy and decreases the risk of intracranial progression compared with standard EGFR-TKIs in NSCLC patients with BM. Our study suggests that osimertinib + bevacizumab ranked the first for PFS, and SoC + PbCT ranks the first for OS in them. Due to immaturity of OS data, the OS comparison among osimertinib + bevacizumab, aumolertinib, and osimertinib was lacking. Previous studies demonstrated that bevacizumab was beneficial for patients with BM,[46-48] our results suggested that osimertinib + bevacizumab was related to the most favorable PFS for those with BM compared with others treatments. However, previous studies observed a shorter PFS with osimertinib plus bevacizumab than osimertinib alone in patients with EGFR T790M-mutated NSCLC, and failed to show the efficacy of osimertinib plus bevacizumab for improving PFS in untreated patiens with EGFR-mutated NSCLC. Further researches were needed to explore the potential population, who can benefit from the regiment of osimertinib plus bevacizumab. Our OS results were consistent with a previous study, in which gefitinib + PbCT was related to the most favorable PFS and OS compared with other therapies in EGFR-mutated NSCLC patients with BM. The reason is not completely clear, and an explanation is possible that the combination of SoC and PbCT has a synergistic effect. A previous study indicated that gefitinib combined with pemetrexed enhanced cell growth inhibition, increased cell death, and prevented gefitinib resistance in EGFR exon 19 deletion NSCLC cell lines. A previous study showed that pemetrexed-cisplatin regimen was also effective and well-tolerated as a first-line therapy for BM, NSCLC patients, with an intracranial ORR and PFS of 41.9% and 4.0 months, respectively. Therefore, it was rational to deduce that EGFR-TKI plus pemetrexed-based chemotherapy showed more favorable efficacy for EGFR-mutated NSCLC patients with BM compared with EGFR-TKI therapy alone (especially first-generation EGFR-TKIs). As direct comparisons between EGFR-TKI plus chemotherapy and osimertinib were limited, our results need to be further validated.
Moreover, we explored different treatments in patients without BM. Osimertinib + bevacizumab was most likely ranked the best in terms of PFS, and SoC + PbCT might be ranked the first in OS. Since the OS data of osimertinib + bevacizumab and aumolertinib were immature, the OS results did not include them. In addition, several studies have confirmed that EGFR-TKIs are better than chemotherapy as a first-line therapy regimen in advanced EGFR-mutated NSCLC patients.[52-56] However, in this study, no significant difference was found between PbCT and SoC in NSCLC patients without BM.
Previous NMA compared current first-line treatment regimens in advanced EGFR-mutated NSCLC patients and indicated that gefitinib combined with pemetrexed-based chemotherapy and osimertinib alone were associated with the most favorable PFS and OS. When including the regimens of osimertinib + bevacizumab and aumolertinib, data from our study suggested that osimertinib + bevacizumab is the optimal treatment regimen for PFS in advanced EGFR-mutated NSCLC patients, SoC + PbCT is still the optimal treatment regimen for OS, and no significant differences are found between SoC + PbCT and osimertinib.
Our study has some limitations. First, all available data in this study were extracted from subgroups of RCTs, which easily leads to a risk of bias. Second, adverse events were not available for analysis in this study because they are mostly available in general populations instead of subgroups. Third, there were some patients who accepted radiotherapy before systemic therapy, which may affect the results. Fourth, there was not further stratified analysis based on EGFR mutation types to explore the optimal first-line therapeutic schedule, limited by the number of studies included. The subgroup analysis in the BRAIN study suggested that patients with EGFR 19 deletion were more likely to benefit from EGFR-TKIs. The median BM-related PFS in patients with EGFR 19 deletion mutation was significantly better than that in patients with L858R mutation (31.8 months vs. 8.3 months, P = 0.03) among NSCLC patients with EGFR mutation and BM, who were treated with osimertinib. Therefore, it is necessary to distinguish different EGFR mutation types. In addition, there were heterogeneities in our analysis to some extent, which are caused by the differences in patient characteristics, the limited number of included RCTs, healthcare systems, and research backgrounds. Thus, we applied a random-effects consistency model to guarantee robustness. Finally, the subsequent therapy of patients was not taken into account in analysis, which would considerably affect the OS.
To summarize, first-line treatments based on different BM statuses need to be considered in practice for advanced EGFR-mutated NSCLC patients. Osimertinib + bevacizumab is probably related to the most favorable PFS in advanced EGFR-mutated NSCLC patients with or without BM. For OS, SoC + PbCT is still most likely to be the preferable regimen regardless of BM status. The combination therapy may be more effective than monotherapy, and osimertinib combined with bevacizumab or chemotherapy is possible to be a new strategy in the future for some subgroups.
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